OBJECTIVE: Clinicians face difficulty in when and in what order to position biologics and JAK inhibitors in anti-TNF refractory ulcerative colitis (UC) patients. We aimed to compare the effectiveness and safety of vedolizumab and tofacitinib in anti-TNF exposed UC patients in our prospective nationwide Initiative on Crohn and Colitis (ICC) Registry. METHODS: UC patients who failed anti-TNF treatment and initiated vedolizumab or tofacitinib treatment, were identified in the ICC Registry in the Netherlands. We selected patients with both clinical as well as biochemical or endoscopic disease activity at initiation of therapy. Patients previously treated with vedolizumab or tofacitinib were excluded. Corticosteroid-free clinical remission (SCCAI≤2), biochemical remission (CRP ≤5 mg/L or fecal calprotectin ≤250 μg/g) and safety outcomes were compared after 52 weeks of treatment. Inverse propensity scores weighted comparison was used to adjust for confounding and selection bias. RESULTS: Overall, 83 vedolizumab and 65 tofacitinib treated patients were included. Propensity score weighted analysis showed that tofacitinib treated patients were more likely to achieve corticosteroid-free clinical remission and biochemical remission at week 12, 24 and 52 compared to vedolizumab treated patients (OR: 6.33, 95%CI:3.81-10.50, P<0.01, OR: 3.02, 95%CI: 1.89-4.84, P<0.01 and OR 1.86, 95%CI: 1.15-2.99, P=0.01 and OR: 3.27, 95%CI: 1.96-5.45, P<0.01, OR: 1.87, 95%CI: 1.14-3.07, P=0.01 and OR:1.81, 95%CI: 1.06-3.09, P=0.03, respectively. There was no difference in infection rate or severe adverse events. CONCLUSION: Tofacitinib was associated with superior effectiveness outcomes compared to vedolizumab in anti-TNF experienced UC patients along with comparable safety outcomes.